The aim of this programme of research is to gain deeper insights into two related areas of cellular immunology, namely the differentiation and diversification of B lymphocytes in the mouse; and the mechanisms by which antigen acts on the various differentiation stages, causing activation and antibody production under some circumstances, but immunological paralysis or tolerance under others. Along this broad theme, we will study lymphocytes fractionated from new born mouse spleen and adult bone marrow, on the basis of their light-scattering characteristics and their amount of surface immunoglobulin to obtain homogeneous populations of cells at various stages of B lymphocyte differentiation. These cells will then be cultured with antigens acting as putative tolerogens, or with purified anti-mouse immunoglobulin antibodies, to determine precisely the sensitivity of the various stages to tolerance induction. Moreover, attempts will be made to show that tolerance induction involves the accumulation of negative signals rather than a destruction of the cell or a modulation or blockade of its surface immunoglobulin receptors.